Biodegradable polymer for marking tissue and sealing tracts

ABSTRACT

A tissue marker formed of a biodegradable polymer having drug-delivery capabilities is combined with a sealant that encapsulates the tissue marker and which serves to help anchor the tissue marker against migration. The sealant is delivered to a site in dehydrated form and moisture inherent in tissue at the site expands the sealant. The expanded sealant is formed of a hydrogel and is therefore more compatible to the surrounding tissue than the material of the tissue marker. The sealant and the tissue marker are both bioabsorbed over time.

CROSS-REFERENCE TO RELATED DISCLOSURES

This disclosure is a divisional application claiming the benefit of thefiling date of pending U.S. patent application entitled: “BiodegradablePolymer for Marking Tissue and Sealing Tracts,” by the same inventors,filed on May 3, 2002, bearing Ser. No. 10/063,620.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates, generally, to a biodegradable tissue marker andsealant. More particularly, it relates to a tissue marker formed of abiodegradable polymer having drug-delivery capabilities. It furtherrelates to a sealant that encapsulates the tissue marker and whichserves to help anchor the tissue marker against migration.

2. Description of the Prior Art

U.S. Pat. No. 6,350,244 entitled Bioabsorable Markers For Use In BiopsyProcedures to the present inventor discloses a bioabsorbable marker thatis positioned near a lesion or tumor during a biopsy procedure. Themarker includes a contrast agent and is bioabsorbed slowly so that thebiopsy site can be located weeks or even months later if needed. U.S.Pat. No. 6,350,244 is hereby incorporated by reference into thisdisclosure, and is hereinafter referred to as the first-incorporatedpatent.

Co-pending U.S. patent application Ser. No. 09/683,282, filed Dec. 7,2001, entitled Bioabsorbable Sealant, also to the present inventor,discloses a sealant that expands upon contact with water or other bodilyfluid. It can also expand upon contact with heat or other stimulus. Thesealant has utility in sealing various openings in the body such as ahole in a lung, an opening in the myocardial septum, and the like. It isalso useful in sealing a blind bore that contains stem cells thatpromote angiogenesis. U.S. patent application Ser. No. 09/683,282 isalso hereby incorporated by reference into this disclosure, and ishereinafter referred to as the second-incorporated disclosure.

Prior to this disclosure, it was not known that the tissue marker of thefirst-incorporated disclosure and the sealant of the second incorporateddisclosure could be combined and used in combination with one another.Anchoring the tissue marker against migration was problematic. Moreover,although the tissue marker included a contrast solution to facilitateits imaging under X-rays, it was unknown how to use the tissue marker orthe sealant as a drug delivery means.

Nor was it known that a tissue marker could be formed into a shape thatwould enable it to serve as its own anchoring means.

Nor was it known how polymers having utility as tissue markers could beformulated to achieve differing degradation rates. More particularly, itwas not known how to make different polymers to contain contrast fordifferent amounts of time, such as one month to six months or more byusing two different polymers.

Nor was it known how to formulate a marker polymer with a therapeuticdrug or other pharmaceutical agent so that the degradation of the markerwould gradually release the drug or agent to a site.

Nor was it known how the polymers could be formulated to exhibitdiffering expansion rates when exposed to water or other liquid fluids.

The sealants of the prior art require in-situ curing. For example, FocalSealant® is an in-situ sealant available from Genzyme Corporation. Priorart sealants such as Focal Sealant require the application of astimulant such as visible light, heat, and the like thereto.

Accordingly, what is needed is a combination tissue marker and sealantthat can be formed into many different shapes and sizes, depending uponthe application, that can degrade at different rates, depending upon theapplication, that can expand in response to moisture or other bodilyfluids at different rates, depending upon the application, and that doesnot require in-situ curing.

There is a need as well for a bioabsorbable tissue marker that candeliver drugs or other therapeutic agents to a site over a prolongedperiod of time.

There is a further need for a sealant that can anchor a tissue markeragainst migration, that can provide a seal for openings in tissue, andthat biodegrades over a period of one to six months or more.

Moreover, there is a need for a combination tissue marker and sealantthat requires no in-situ curing as aforesaid and which thereforerequires no initiators, buffers or other chemicals, proteins, enzymes,visible light, UV, accelerator, nor addition of foreign chemicals intothe body.

A need also exists for a means for making tissue markers more compatiblewith surrounding tissue. Tissue markers are hard and have littlecompatibility with surrounding tissue. Thus there is a need for acushioning means that surrounds a marker and which provides a morecompatible interface means with surrounding tissue.

Biodegradable polymers in general have been used in many medical devicesand implant applications. For example, they have been used as orthopedicimplants, tissue sealants, sutures, and as ligating clips. The medicaldevices incorporating these polymers are made, primarily, ofbiodegradable materials such as poly(dioxanone) (PDO), polyethyleneglycol (hydrogels, polylactides (PLA), polyglycolides (PGA),polycaprolactone (PCL), and their copolymers. Some of the polymers, suchas hydrogels, are hydrophilic. Others such as PCL are hydrophobic.Because these polymers degrade by hydrolysis, the type of polymer andits physical form used in a particular application has an effect indefining the degradation period.

Traditional brain tumor treatment includes surgery, radiotherapy, andchemotherapy. Alternative strategies are needed due to the high rate ofrecurrence of tumors after such treatment and their resistance toradiation and cytostatics. In the recent past, gene therapy treatmentssuch as reversion of the malignant phenotype by down regulation of theoncogene expression or insertion of normal tumor suppression genes havebeen tried. One challenge with gene therapy treatments concerns theprevention of immunorejection of genetically modified cells afterintracranial implantation. A further challenge is to achieve efficientgene transfer, as well as prolonged gene expression within the relevantcells.

Numerous other surgical procedures would be facilitated by tissuemarkers that degrade over predetermined periods of time, that includecontrast agents so that they can easily be found, that do not migrate,that interface well with surrounding tissue, and that deliver drugs orother therapeutic agents to a site over a predetermined length of time.

In view of the prior art considered as a whole at the time the presentinvention was made, it was not obvious to those of ordinary skill in thepertinent art how the identified needs could be fulfilled.

SUMMARY OF THE INVENTION

Biodegradable polymers and co-polymers are combined with or withoutionic and non-ionic contrast agents, depending upon the application. Forexample, no contrast agent is needed in an application where there is noneed to view a site at a later date.

The novel formulations that include contrast agents are designed toallow the radiopacity of the markers to last for an extended period oftime so that they can be seen under X-ray or other imaging means forfurther diagnostic or intervention procedures at a date that may beweeks or months after implanting of the marker.

The novel plug is treated so that it is visible under ultrasound,magnetic resonance imaging, and other imaging techniques if anapplication requires such visibility. Accordingly, it may contain or beimpregnated with a contrast solution containing radium, iodine,beryllium, or other contrasting agent.

The plug is impregnated with a contrasting agent to facilitate detectionof the plug by imaging means selected from the group of imaging meansconsisting of magnetic resonance imaging, ultrasound, Doppler, androentgenological means including x-ray, computed axial tomography (CAT)scanning, also known as CT scan, mammography, and fluoroscopy, or otherknown or hereafter known imaging techniques.

The plug may also include a radioactive substance detectable by aradiation detecting means including a gamma counter and a scintillationcounter. In another alternative, the plug includes a transmitting meansadapted to transmit signals in the electromagnetic spectrum that aredetectable by receivers adapted to receive signals in theelectromagnetic spectrum.

The novel polymers are based upon well-known polymers such aspolyactides (PLA), including polylactic acid, for example,polyglycolides (PGA), including polyglycolic acid, for example,polycaprolactone (PCL), poly(dioxanone) (PDO), collagen, renaturedcollagen, gelatin, renatured gelatin, crosslinked gelatin, and theirco-polymers. The blend of polymers and copolymers is designed to degradeas a result of hydrolysis of polymer chains into biologically acceptableand progressively smaller components such as polylactides,polyglycolides, and their copolymers. These break down eventually intolactic and glycolic acid, enter the Kreb's cycle and are broken downinto carbon dioxide and water and excreted.

Some of these polymers and copolymers do not possess the mechanicalproperties that are required for certain applications. For example, asimplants for soft tissue PGA, PLA, PCL, PDO and their copolymers mayrequire increased flexibility and a modulus of elasticity that is closerto soft tissue. Some hydrogels, due to their water content, provide amore flexible structure that is similar to soft tissue. Therefore, bycombining the polymers that lack certain required mechanical propertiessuch as a suitable modulus of rigidity or modulus of elasticity withhydrogels, suitable degradation and drug delivery properties areobtainable and an exterior is achieved that has mechanical propertiessimilar to the mechanical properties of soft tissue.

PLA, PGA, PCL, PDO and their copolymers are designed to provide asustainable and gradual degradation and therefore slow release of drugswith the degradation of the polymer substrate. Hydrogels are notsuitable for prolonged drug delivery without using additional bonding ofthe drug to the hydrogels especially with small size moleculepharmaceutical agents.

Thus it is understood that a primary teaching of this invention relatesto biodegradable polymers having utility as tissue markers as taught bythe first-incorporated patent and as sealants as taught by thesecond-incorporated disclosure. When combined, the tissue marker andsealant serve as a drug-delivery means as the substrate of the polymerdegrades. Advantageously, the expanded sealant prevents migration of themarker as well, and provides a soft interface means between the markerand surrounding soft tissue.

More particularly, poly (DL-lactide) is used to provide a biodegradablesubstrate that allows slow degradation. However, it swells as water orother bodily fluid penetrates into the substrate. Different molecularweights could be used to achieve a different hydration rate. Delayedhydration provides a better visualization under ultrasound when furtherdiagnosis or intervention is required.

An alternative method for achieving a different degradation rate is toemploy a biodegradable hydrophobic polymer coating to delay thepenetration into the substrate by water or other bodily fluid. Thehydrophobic coating may be sprayed onto the substrate or the substratemay be dipped into the coating. Either way, the thickness of the coatingis controlled because a thicker coating resists penetration for a longertime than a thinner coating. Polycaprolactone (PCL) degrades nicely, forexample, and therefore works well when sprayed or coated onto thesubstrate. Teflon® does not work because it forms a substantiallypermanent shield.

When anchoring an implant in a specific area is required, aPGA/PLA/PCL/PDO based polymer combined with a contrast agent forvisibility if required for a particular application is encapsulatedwithin a hydrogel such as a PEG-based hydrogel. The encapsulation isaccomplished by any suitable means such as mechanically combining thetissue marker and sealant in a mold, by compression, and the like. Thehydrogel part of the combined polymer is dehydrated and delivered to thetarget site. Hydration of the polymer causes its expansion and thusprovides a mechanical anchoring of the implant in the tissue. Theseproperties are attained by combining the teachings of the first andsecond-incorporated disclosures. Where the polymer is used as a tissuemarker, it is molded or extruded into different shapes to provideanchoring properties.

The contrast agent, if provided, is also accompanied by or replaced withdifferent pharmaceutical agents such as anti-cancer drugs, antibiotics,anti-inflammatory drugs and the like that are slowly released usingPGA/PLA/PCL/PDO substrates of the first-incorporated disclosure whilethe hydrogels of the second-incorporated disclosure provides a suitableanchoring means. The degradation of the external hydrogel may also betailored to have a prolonged degradation time while the PGA/PLA/PCL/PDOcombined with a drug agent could be degraded at a faster rate.

Examples of suitable bioabsorbable materials that expand when contactedby water include hydrogels, collagen, polysalactic acid, and any othersuitable hydrophilic agents.

Examples of polymers that swell in the presence of aqueous fluids suchas biological fluids will now be disclosed. Virtually all of thefollowing polymers are hydrogels. Synthetic hydrogels can be preparedfrom the following classes of polymers and these are generallyconsidered to be non-biodegradable:

poly(hydroxyalkyl methylacrylates) such as poly(glyceryl methacrylate)

poly(acrylamide) and poly(methacrylamide) and derivatives

poly(N-vinyl-2-pyrrolidone)

anionic and cationic hydrogels

poly(vinyl alcohol)

poly(ethylene glycol) diacrylate and derivatives from block copolymerscomposed of poly(ethylene oxide)-poly(propylene oxide)-poly(ethyleneoxide) and poly(propylene oxide)-poly(ethylene oxide)-poly(propyleneoxide) blocks, respectively;

All of the above can be cross-linked with agents such as ethylene glycoldimethacrylate or methylene-bis-acrylamide.

Biodegradable synthetic hydrogels can be prepared from polymers such asthose listed above by incorporating one or more of the followingmonomers:

Glycolide, Lactide, e-Caprolactone, p-Dioxanone and TrimethyleneCarbonate

In addition, biodegradable hydrogels can be based on natural productssuch as the following:

Polypeptides such gelatin which may be cross-linked with formaldehyde orglutaraldehyde and various other dialdehydes.

Modified chitin hydrogels, which may be prepared from partiallyN-deacetylated chitin which, may then be cross-linked with agents suchas glutaraldehyde.

Dextran, a polysaccharide, can be derivatized with groups such as3-acryloyl-2-hydroxypropyl esters and subsequently cross-linked by freeradical copolymerization with N′,N′-methylenebisacrylamide.

Starch may be similarly derivatized or using glycidyl acrylate followedby free radical cross-linking as described above.

The plug is impregnated with a contrasting agent to facilitate detectionof the plug by imaging means selected from the group of imaging meansconsisting of magnetic resonance imaging, ultrasound, Doppler, androentgenological means including x-ray, CT scan, mammography, andfluoroscopy.

Suitable contrast agents include a colored substance such as a dye orcolorant such as methylene blue, gentian violet, indigo, dyes used intattooing or colorant particles such as India, indigo, carbon particlesor carbon preparations described in Langlois, S. L. P. and Carter, M. L.Carbon Localization of Impalpable Mammographic Abnormalities, AustralisRadiol. 35:237-241 (1991) and/or Svane, G. A. Stereotaxis Technique forPreoperative Marking of Non-Palpable Breast Lesions, Acta Radiol. 24(2):145-151 (1983). Chemical compounds that serve as suitable contrastagents include AgCl, Agl, BaCO₃ BaSO₄, K, CaCO₃, ZnO, Al₂O₃, AGNO₃,ammonium salts, sodium salts, potassium salts, ethiodized oil, isohexyl,isopamidol, gas, lipid, oil, and all possible combinations thereof.

Alternatively, the plug includes a radioactive substance detectable by aradiation detecting means including a gamma counter and a scintillationcounter. In another alternative, the plug includes a transmitting meansadapted to transmit signals in the electromagnetic spectrum that aredetectable by receivers adapted to receive signals in theelectromagnetic spectrum.

This invention further includes the fabrication of tubular implants forimplanting in tubular organs. Such a structure includes a lumen definedby a PGA/PLA/PCL/PDO polymer and a hydrogel that provides the exteriorof the implant. Thus, as the hydrogel expands upon contact with a liquidfluid, it anchors itself into the surrounding tissue. The inner layer ofthe hydrogel contains a circular solid polymer made of PGA/PLA/PCL/PDOas a structural support to maintain an open lumen. The lumen remainsopen even when the hydrogel has fully expanded because the expansion isradially outward, away from the PGA/PLA/PCL/PDO polymer substrate thatdefines the lumen. A drug or drugs may be added to the polymer substrateso that said drug or drugs are delivered over time to the patient as thesubstrate degrades. As mentioned above, in most cases the polymersubstrate is designed to degrade at a rate faster than the degradationrate of the hydrogel cover.

The primary object of this invention is to provide a combination tissuemarker and sealant that prevents migration of the marker.

Another important object is to provide biodegradable polymers thatperform the functions of marking a site, delivering drugs or othertherapeutic agents to a site, and sealing openings or tracts left by abiopsy procedure or other surgical procedure.

Another object is to provide a hydrophobic coating that extends thedegradation rate by shielding the substrate from moisture or bodilyfluids for a predetermined time.

Another important object is to provide a combination tissue marker andsealant that does not require in-situ curing.

Yet another important object is to encapsulate a tissue marker in asealant material that is more compatible to soft tissue than is a tissuemarker.

These and other important objects, advantages, and features of theinvention will become clear as this description proceeds.

The invention accordingly comprises the features of construction,combination of elements, and arrangement of parts that will beexemplified in the description set forth hereinafter and the scope ofthe invention will be indicated in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and objects of the invention,reference should be made to the following detailed description, taken inconnection with the accompanying drawings, in which:

FIG. 1A is a perspective view diagrammatically depicting the tissuemarker material in the form of a solid rod. It may also be interpretedas depicting said tissue marker material in the form of a hollowcylinder;

FIG. 1B is a side elevation view diagrammatically depicting the markermaterial in solid rod form or in hollow cylindrical form, depending uponthe interpretation of the drawing;

FIG. 1C is a perspective view diagrammatically depicting the sealantmaterial in solid rod form;

FIG. 1D is a side elevation view diagrammatically depicting the sealantmaterial in solid rod form;

FIG. 1E is a perspective view diagrammatically depicting the marker ofFIG. 1A housed within the sealant of FIG. 1C, in a rod-in-rodarrangement;

FIG. 1F is a side elevation view that diagrammatically depicts a markerof FIG. 1A or 1B encapsulated within the sealant material of FIG. 1D;

FIG. 2A is a side elevation view diagrammatically depicting the markermaterial formed into a dog bone shape and ensleeved within the sealantmaterial of FIG. 1E;

FIG. 2B is a side elevation view diagrammatically depicting the markermaterial of FIG. 2A encapsulated within the sealant material of FIG. 1F;

FIG. 3A is a longitudinal sectional view depicting the marker of FIG. 1Aensleeved within the sealant material of FIG. 1C in a tube-in-tubearrangement;

FIG. 3B is an end view of the parts depicted in FIG. 3A;

FIG. 4A is a longitudinal sectional view depicting a pair of the markersof FIG. 1A ensleeved within a double-lumened sealant material indehydrated form;

FIG. 4B depicts the parts of FIG. 4A when the sealant material ishydrated;

FIG. 4C is similar to FIG. 4B except it depicts the sealant materialhaving lumens that are larger in diameter than the lumens of FIG. 4A andFIG. 4B;

FIG. 5 is a side elevation view of a marker or sealant having a pointeddistal end;

FIG. 6 is a side elevation view of a marker or sealant having aharpoon-shaped distal end;

FIG. 7 is a side elevation view of a marker or sealant having a“U”-shaped or clip-shaped configuration;

FIG. 8 is a side elevation view of a marker or sealant like that of FIG.7 but further equipped with a latch means;

FIG. 9 is a side elevation view of a sealant having marker particlesembedded therein;

FIG. 10 diagrammatically depicts the combination marker and sealant whenused to seal a liver biopsy tract;

FIG. 11A is a longitudinal sectional view of an artery depicting how asection thereof is expanded by an angioplasty procedure;

FIG. 11B is a view like FIG. 11A and adds a longitudinal sectional viewof the combination marker and sealant of this invention positioned insaid expanded section of said artery;

FIG. 11C is a cross-sectional view of the sealant when hydrated and inannular form;

FIG. 11D is a view like FIG. 11A and depicts a plurality of thering-shaped sealants of FIG. 11C disposed in supporting relation to saidexpanded area of said artery, said sealants being used in conjunctionwith a metallic stent;

FIG. 11E is an end view depicting a tube-in-tube-in-tube arrangementwhere the marker of FIG. 1A ensleeves a first sealant of tubularconfiguration and is ensleeved by a second sealant of tubularconfiguration having a diameter larger than the diameter of the firstsealant;

FIG. 12A is a diagrammatic view of a prostate gland and a urethra;

FIG. 12B is a sectional view taken along line 12B-12B in FIG. 12A;

FIG. 12C is a diagrammatic view of the prostate gland of FIG. 12A aftera tissue reduction procedure has been performed;

FIG. 12D is a sectional view taken along line 12D-12D in FIG. 12C;

FIG. 12E is a diagrammatic view like that of FIG. 12C, depicting thecombination marker and sealant positioned in structural support relationto the excised part of the gland;

FIG. 13 is a diagrammatic view of the marker and sealant combinationwhen positioned at the juncture of a bladder and a urethra;

FIG. 14 is a diagrammatic view of the marker and sealant combinationwhen used in a biliary tract; and

FIG. 15 is a diagrammatic view of the marker and sealant combinationwhen used in a fallopian tube.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

How to achieve non-covalent bonding of ionic and non-ionic contrastagent with polymers such as PGA/PLA/PCLUPDO will now be described.Different techniques are employed to accomplish similar results inconnection with covalent bonding.

The starting materials employed in this invention for synthesizing thenovel tissue marker include poly(DL-lactide), inherent viscosity (IV) of0.63 dL/g (where the solvent is CHCl₃ and the concentration isapproximately 0.5 g/dL at 30° C.), 50/50 poly(DL-lactide-co-glycolide,IV of 0.17 dL/g (hexafluoroisopropanol, concentration ˜0.5 g/dL at 30°C.) and 75/25 poly(DL-lactide-co-glycolides), having IVs of 0.44 dL/g(CHCl₃, concentration ˜0.5 g/dL at 30° C.) and 0.69 dL/g (CHCl₃,concentration ˜0.5 g/dL at 30° C.). These materials are commerciallyavailable from Birmingham Polymers, Inc., of Birmingham, Ala.

Further starting materials for synthesis of the novel tissue markerinclude poly(DL-lactide), IV of 1.6 dL/g (CHCl₃, concentration 0.1% at25° C.), commercially available from Boehringer Ingelheim of Petersburg,Va., under the trademark RESOMER® R 207. Contrast agents sodiumdiatrizoate and5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N′-bis(2,3-dihydroxypropyl)isophthalamide (iohexyl) is commericially available from Sigma ChemicalCo. of Milwaukee, Wis. Glycolide and DL-lactide monomers arecommercially available from Purac America Inc. of Lincolnshire, Ill.1-Dodecanol and ε-caprolactone are commercially available from AldrichInc. of Milwaukee, Wis. Tin (II) 2-ethylhexanoate is commerciallyavailable from Air Products and Chemicals, Inc. of Allentown, Pa.DL-lactic acid (JT Baker reagent) is commercially available from VWRScientific of Bridegeport, N.J. Solvents such as tetrahydrofuran (THF),toluene, methanol, and hexanes of reagent grade or better arecommercially available from multiple well-known sources.

As a first example, synthesis of 75/25poly(DL-lactide-co-ε-caprolactone) copolymer, hereinafter referred to as75/25 (DL-PLC1, is performed by charging 22.5 grams of ε-caprolactone,310 mls of toluene, 0.422 grams in 3.02 mls of tolulene solution of1-dodecanol and 0.382 grams in 2.34 mls of tolulene solution of stannousoctoate catalyst into a one liter, three neck, round bottom flask. Thereaction solution is placed in an argon atmosphere, stirred with anoverhead stirrer that includes a glass stirrer shaft equipped with aTeflon® blade and approximately 100 mls of the solvent is distilled offat atmospheric pressure. The reaction temperature is lowered toapproximately 90° C. and 67.5 grams of solid DL-lactide is added to thesolution in one portion. The reaction temperature is raised toapproximately 110° C. to afford a gentle reflux. After forty eight hoursat that temperature, heating is discontinued and the reaction solutiontemperature is allowed to fall to 75°. The solution is diluted with 600mls of toluene and stirred at 55-60° for 1.5 hours. The diluted reactionsolution is transferred into a crystallizing dish and the polymer isprecipitated with one liter of hexanes. The supernatant is then decantedoff and the viscous residue dried for one to three days under a vacuumat 40° C. to a constant weight. The solid polymer is removed from thedish and stored under an argon atmosphere at −30° C.

Synthesis of 20/80 poly(DL-lactite-co-ε-caprolactone), hereinafterreferred to as 20/80 DL-PLCl and 10/90poly(glycolide-co-ε-caprolactone), hereinafter referred to as 10/90 PGClcopolymers are prepared by the same process used for the preparation of75/25 DL-PLCl in the first example, with the exception that, in the caseof the 20/80 DL-PLCl copolymer, DL-lactic acid is used as the initiatorinstead of 1-dodecanol. The contents of each monomer in the finalpurified polymers are determined by high resolution proton nuclearmagnetic resonance spectroscopy and these are summarized in Table 1.That table further includes the melting points for 20/80 DL-PLCl and10/90 PGCl copolymers, which are obtained by differential scanningcalorimetry (DSC). TABLE 1 Chemical and Physical Properties of theSynthesized Polymers Copolymer Composition, Weight % Melting Point Mol.Wt. Polymer Glycolide DL-Lactide ε-Caprolactone ° C. Mn¹ 20/80 DL-PLC1 —20 80 46 40-70K 75/25 DL-PLC1 — 75 25 Amorphous 20-30K 10/90 PGC1 9.4 —90.6 55 30-60K¹Molecular weights were determined by GPC using methylene chloridesolvent and polystyrene standards.

In a third example, the 75/25 poly(DL-lactide-co-glycolide) with iohexylis formulated by preparing a 2% by weight over volume solution of theiohexyl contrast agent by mixing 5.15 grams of the solid contrast agentin 130 mls of methanol in a 500 ml Erlenmeyer flask for 5-10 minutesuntil the solid is fully dissolved. The solution is then diluted with130 mls of tetrahydrofuran (THF) to provide the 2% solution. A 6%solution of the biodegradable polymer is prepared in a one literErlenmeyer flask by addition of 330 mls of THF to 20.6 grams of thesolid 75/25 DL-PLG polymer. The mixture is stirred with gentle heating(30-40° C.) until the solid is dissolved. The entire contrast solutionis then slowly poured into the stirred polymer solution to give asingle-phase solution of the polymer and the contrast agent. Thecombined solution is stirred for an additional five minutes and then thepolymer and contrast agent are co-precipitated with hexanes. Theprecipitation is achieved by rapid addition of two volumes of hexanes toa rapidly mixed solution of the polymer/contrast solution. The mixtureis again stirred for an additional five minutes and then allowed to situnstirred at room temperature for five to ten minutes to allow the solidto settle to the bottom of the flask. The supernatant is then decantedand discarded and the semi-solid residue is dried under vacuum for oneto two days at 40° C. to a constant weight. Quantitative recovery of100.8% of the solids is obtained for the polymer and the contrast agentin this example. The solid, which is used for fabrication of the novelmarkers, contains 20% by weight of contrast agent as a homogenousmixture with the biodegradable polymer.

To study the effect of the contrast agent content in the biodegradablemarkers on their visualization under X-ray imaging, two different DL-PLGpolymers are formulated with the iohexyl contrast agent in which thecontrast is varied between 5 and 40% by weight. These markers areformulated by a procedure similar to the procedure for the markerprepared in the third example. The composition of these biodegradablemarker solids is summarized in Table 2. The recovery of the solids afterthe hexanes precipitation step is greater than 97% for all of the markercompositions listed in Table 2. TABLE 2 Compositions of theBiodegradable Markers Source and Inherent Viscosity Contrast AgentContrast Content Polymer Lot # dL/g Type Name %(w/w) 50/50 DL-PLGBPID00120 0.17 Non-ionic Iohexol 5 50/50 DL-PLG BPID00120 0.17 Non-ionicIohexol 10 50/50 DL-PLG BPID00120 0.17 Non-ionic Iohexol 20 50/50 DL-PLGBPID00120 0.17 Non-ionic Iohexol 30 50/50 DL-PLG BPID00120 0.17Non-ionic Iohexol 40 75/25 DL-PLG BPID98054 0.44 Non-ionic Iohexol 575/25 DL-PLG BPID98054 0.44 Non-ionic Iohexol 10 75/25 DL-PLG BPID980540.44 Non-ionic Iohexol 20 75/25 DL-PLG BPID98054 0.44 Non-ionic Iohexol30 75/25 DL-PLG BPID98054 0.44 Non-ionic Iohexol 40

The contrast solution may also be an ionic contrast solution such assodium diatrizoate, for example.

The novel biomarkers may be fabricated by extrusion, injection molding,or compression molding. Multiple sizes and shapes may be fabricatedusing these or similar manufacturing processes. By controlling pressure,temperature, and extrusion speed rate during the extrusion process,differing sizes and properties are obtainable. During the development ofthis invention, different extrusion and compression molding processeswere used to fabricate the markers.

The novel biomarkers and the novel sealant material may be combined in avariety of fabrication processes. During the development of thisinvention, insert molding was used to combine the marker and the sealantto one another. Different sizes and shapes having differing propertiesmay be manufactured using insert injection and compression molding, forexample.

To extend the biodegradable marker's range of properties such asdegradation times, ability to be visualized under ultrasound, hardnessand fabrication temperatures, marker solids are prepared from additionaltypes of polymers with both ionic and non-ionic contrast agents asindicated in Table 3. Most of these biodegradable markers are formulatedwith 20% contrast agent. The recovery of the solids after the hexanesprecipitation step is greater than 91% in all of these formulations.TABLE 3 Compositions of the Biodegradable Markers Source and InherentViscosity Contrast Agent Contrast Content Polymer Lot # dL/g Type Name%(w/w) DL-PLA BI 260911 1.6 Ionic Sodium Diatrizoate 10 DL-PLA BI 2609111.6 Ionic Sodium Diatrizoate 20 DL-PLA BI 260911 1.6 Non-ionic Iohexol10 DL-PLA BI 260911 1.6 Non-ionic Iohexol 20 DL-PLA BPI D00004 0.63Non-ionic Iohexol 20 PGC1 See example 3 — Non-ionic Iohexol 2020/80DL-PLC1 See example 3 — Non-ionic Iohexol 20 20/80DL-PLC1 Seeexample 3 — Ionic Sodium Diatrizoate 20 75/25DL-PLC1 See example 3 —Non-ionic Iohexol 20

The type of polymer used can be any of the biodegradable polymers suchas other PLGA polymers, e.g., 50/50 DL-PLGA, 50/50 L-PLGA, etc., or theL-PLCl, PGCl, etc.

The contrast agent can be formulated in these polymers at anyconcentration ranging from 0 to 50% by weight, but preferably at 70% byweight. (That statement contradicts itself).

The solvent combinations can also be varied as well as the precipitationmethods.

There are many applications for the novel implants. For example, duringdiagnosis of hepatic carcinoma or other hepatic disease using a liverbiopsy under CT visualization, a biopsy tract is formed. The tract maybe plugged to prevent bleeding by using the above-mentionedPGA/PLA/PCL/PDO based polymer combined with a contrast agent forvisibility and encapsulated within a hydrogel. Drugs or any otherpharmaceutical agents could be delivered to the liver by replacing thecontrast agent with such drugs or agents.

As another example, a heart biopsy may be conducted near diseased hearttissue using a mechanical biopsy gun. The biopsy tract or tracts arethen filled with different growth factors and stem cells to promoteangiogenesis in the heart muscle tissue. One method for sealing thetract so that the stem cells and growth factor are constrained to stayin the biopsy tract for a prolonged period of time is disclosed in thesecond-incorporated disclosure. The present disclosure teaches theintegration of two polymers where a PGA/PLA/PCL/PDO with a drug agent isencapsulated within a dehydrated hydrogel. The dehydrated hydrogelbecomes hydrated within a few minutes and its expansion provides ananchoring means.

This invention also has utility in connection with prostate cancerbiopsies where a biopsy needle is inserted though the rectum into theprostate gland under ultrasound visualization. Introduction into thebiopsy tract of a sealing means by means of a coaxial needle willprevent leakage through the bowel into the prostate. Moreover, the plugmay be used to deliver drugs or other therapeutic agents.

Similarly, the novel plugs have utility in connection with the sealingof cavities formed in a prostate gland by tissue reduction proceduresundertaken after a diagnosis of BHP. Different drug agents are releasedover time to reduce inflammation or any other side effects.

In another application, a tubular urethral stent has a thin wall formedof a PGA/PLA/PCL/PDC/PDO polymer substrate with or withoutpharmaceutical agents. A layer of dehydrated hydrogel covers the thinwall but does not block the lumen of the tube. The stent is introducedinto the urethra and the hydrogel expands radially outwardly, anchoringto the urethral wall. This procedure is similar to the conventionalplacement of a urethral stent, but it is more advantageous because it isnot permanent like metallic stents and does not require in situ curinglike other biodegradable stents.

The marker material that forms the inner tube also provides adrug-delivery means for the benefit of the patient.

Growth factors or pharmaceutical agents encapsulated within the novelpolymers may be used advantageously in the treatment of malignant braintumors. The combination marker and sealant of this invention has utilityin the context of gene therapy treatment as the carrier for thebio-active agents and as the anchoring means to position and secure themarker to the target area.

The polymers disclosed herein are formulated to exhibit differingproperties depending upon the application. Some are designed to degrademore slowly than others, some are more hydrophilic or more hydrophobic,and so on. In most applications, the contrast agent-containing polymersare formulated so that the marker is visible under X-ray and/or otherimaging means for one month to six months or even longer.

Turning now to the drawings, FIG. 1A depicts a tissue marker made inaccordance with the teachings of the first-incorporated disclosure. Itis provided in the form of a solid rod 10. Its interior is filled with acontrast agent or other pharmaceutical agent. FIG. 1B depicts marker 10in solid rod form.

FIG. 1C depicts a hydrogel-based sealant 12 made in accordance with theteachings of the second-incorporated disclosure. In this embodiment, itis of hollow cylindrical or tubular construction and is made ofhydrogels. FIG. 1D depicts sealant 12 in solid rod form.

FIGS. 1E and 1F depict the basic conception behind the presentdisclosure which teaches the combination of marker 10 and sealant 12 ofthe incorporated disclosures. The combination marker and sealant member14 of FIG. 1E has an interior 10 formed of the FIG. 1B solid rod markerand an exterior housing 12 formed of the FIG. 1C sealant. In FIG. 1E,marker 10 is co-extensive with sealant 12. In FIG. 1F, interior marker10 is again formed in the solid rod structure of FIG. 1B, but said solidrod 10 has an extent less than that of sealant 12 so that it isencapsulated therein as depicted.

The novel combination marker and sealant member 14 is delivered to asite that requires sealing; the sealant is in dehydrated condition whendelivered to the site. The sealant expands when activated by contactwith water or moisture. The expansion of the hydrogel-based sealant 12holds it in place. The contrast agent in marker 10 facilitates viewingof the site under various imaging techniques for a prolonged period oftime. Marker 10 may also include therapeutic agents that are releasedover time as marker 10 is bioabsorbed. Hydrogels 12 are also bioabsorbedover time, but the time for such absorption is selected to exceed thatof the absorption time of marker 10 if required by an application.

FIG. 2A depicts a marker 10 having bulbous anchoring means at itsopposite ends that extend beyond the opposite ends of hydrogel housing12. FIG. 2B depicts marker 10 having said bulbous anchoring means whenfully encased within hydrogel housing 12.

FIG. 3A is a side elevational view depicting a tube-in-tube arrangementwhere marker 10 is provided in tubular form and is ensleeved withinsealant 12 which is also provided in tubular form. FIG. 3B provides anend view thereof.

Sealant 12 has a pair of open lumens in the embodiment of FIGS. 4A-C,and each of said open lumens has a marker 10 positioned therewithin. Thesealant material of which outer housing 12 is formed is depicted indehydrated form in FIG. 4A. In

FIGS. 4B and 4C, the sealant has expanded due to hydration. In theembodiment of FIG. 4B, the lumen is small and in the embodiment of FIG.4C the lumen is large.

In addition to the cylindrical and rod-shaped markers 10 of FIGS. 1A and1B, marker 10 could also be provided in the form of a rod having apointed leading end as depicted in FIG. 5. The pointed leading end couldserve as an anchoring means that prevents migration of marker 10 fromits intended location.

The harpoon shape of the leading end of the marker depicted in FIG. 6would also provide an anchoring means.

The embodiment of FIG. 7 provides a U-shaped tissue marker 10. This clipshape also has utility as an anchoring means. When the tissue marker isshaped such that it is self-anchoring, the hydrogel sealant is notrequired unless there is a need to seal a surgical or trauma-createdopening.

A latch means is added to the embodiment of FIG. 7 to produce theembodiment of FIG. 8. The latch means is provided to enhance theanchoring of marker 10.

Hydrogel sealant 12 may also be provided in the form of a rod, tube,pointed rod, harpoon, clip, latched clip, and the like.

Moreover, as depicted in FIG. 9, tissue marker particles, collectivelydenoted 10 a, may be dispersed within sealant 12. Such dispersal oftissue marker particles 10 a within hydrogel sealant 12 may be appliedto any form of hydrogel 12. For example, marker particles 10 a could bedispersed throughout a harpoon-shaped sealant 12, a “U”-shaped sealant12, and so on.

The number of shapes is inexhaustible and these Figures are not intendedto illustrate all possible shapes within the scope of this invention butare intended as exemplary only. The novel combined marker and sealantcan be manufactured in any geometrical shape and size and the inventionis not limited to the finite number of examples provided herein.

Six (6) examples of applications for the novel marker/sealantcombination will now be disclosed.

FIG. 10 depicts a hepatic (liver) biopsy. Bore 20 is formed in liver 22by the biopsy procedure. Plug 24 seals the bore at its surface toprevent bleeding at the biopsy site. Plug 24 may be formed of expandablesealant material 12 only so that it expands to securely seal the openingwhen contacted by bodily moisture, or it may include a marker 10 ormarker particles 10 a housed within expandable hydrogel sealant material12. These markers have utility for viewing or drug delivery or both.

A diagrammatic longitudinal sectional view of an expanded artery afteran angioplasty procedure is denoted 24 in FIG. 11A. Hydrogel sealant 12,in tubular form, is initially positioned within lumen 25 of the arteryin unhydrated form; it then expands to the position depicted in FIG. 11Bto hold the artery open. Marker material 10, also in tubular form, ispositioned radially inwardly of sealant 12 and provides supporttherefor.

In the alternative, expandable sealant material 12 may be provided inannular, i.e., ring form as depicted in FIG. 11C and a plurality of saidrings may be disposed in longitudinally and equidistantly spacedrelation to one another along the extent of the expanded section ofartery, in transverse relation to the longitudinal axis of the artery,as indicated in FIG. 11D. Moreover, as depicted in FIG. 11E, markermaterial 10 in annular form may be sandwiched between inner and outerlayers of sealant material 12. Where the bioabsorbable marker materialcontains a contrast agent, the location of the site is made apparentunder imaging for a prolonged period of time. Where therapeutic agentsare contained within the marker material, a time-release of said agentsis provided as the marker material is slowly bioabsorbed.

Still another application for the novel combination of materials isdepicted in FIGS. 12A-F. FIG. 12A diagrammatically depicts a prostategland 30 and a urethra 32 in perspective and FIG. 12B provide s adiagrammatic cross-sectional view thereof. If gland 32 is enlarged, acondition known as BHP, it can compress the urethra and cause arestricted urine flow. As indicated in FIG. 12C, the condition issurgically treated by removing the part of gland 30 that is applyingpressure to urethra 32; the resulting opening is denoted 34 in FIGS. 12Cand 12D. FIG. 12E indicates how a tubular-in-configuration marker 10 ishoused within a tubular-in-configuration sealant 12 to provide supportfor said sealant and to provide a slow delivery of therapeutic agents tothe surgical site. The moisture-activated expansion of sealant 12anchors it to urethra 32 and to prostate gland 30. The urethra isusually damaged during TURP. The lumen serves as a temporary urethrauntil the prostate grows back.

FIG. 13 depicts an application where drugs or other pharmaceuticalagents are delivered to a bladder 40. This is a tube-in-tube-in-tubearrangement where a first tubular section of sealant material 12 isentubed within a tubular section of marker material 10 which is entubedwithin a second section of sealant material 12. The structure indehydrated condition is positioned at the neck of bladder 40 where itjoins urethra 32. Upon activation, sealant material 12 expands to securethe marker 10 in position. As sealant 12 is bioabsorbed, drugs fortreatment of bladder disease are released from said sealant 12 andadministered to the bladder. Pharmaceutical agents of smaller molecularsize could be carried by bioabsorbable marker 10.

The novel sealant, when hydrated, makes the site more visible underultrasound.

FIG. 14 depicts a biliary tract 50 where an opening therein is sealed bythe structure depicted in FIGS. 3A and 3B, i.e., tubular marker 10 ishoused within tubular sealant 12 in a tube-in-tube arrangement. The openlumen of marker 10 enables fluid to flow through the structure. As inthe other embodiments, sealant 12 expands in response to contact withmoisture to hold the tube-in-tube structure in position and marker 10contains either contrast agent or therapeutic agents, or both, forgradual release as the tube-in-tube structure biodegrades.

The same tube-in-tube structure may be used to seal openings infallopian tubes 60 a, 60 b, as diagrammatically depicted in FIG. 15.

The invention is not limited to liver, artery, prostate gland, bladder,biliary tract and fallopian tube applications. In view of theseexemplary applications, other applications will become apparent to thoseof ordinary skill in the medical arts. Expandable sealant material 12has utility in sealing any opening and in providing an anchoring meansfor the marker material even if no sealing is required. The markermaterial may contain a contrast agent or a therapeutical agent, or both,that are released over time as the marker is bioabsorbed.

It will thus be seen that the objects set forth above, and those madeapparent from he foregoing description, are efficiently attained. Sincecertain changes may be made in the above construction without departingfrom the scope of the invention, it intended that all matters containedin the foregoing description or shown in the accompanying drawings shallbe interpreted as illustrative and not in a limiting sense.

It is also to be understood that the following claims are intended tocover all of the generic and specific features of the invention hereindescribed, and all statements of the scope of the invention that, as amatter of language, might be said to fall therebetween.

Now that the invention has been described,

1. A method for performing a hepatic biopsy, comprising the steps offorming a bore in a liver by a biopsy procedure, providing a plug formedof an expandable sealant material, and sealing said bore at its surfacewith said plug to prevent bleeding, said plug expanding to securely sealthe opening when contacted by bodily moisture.
 2. The method of claim 1,further comprising the step of including a marker housed within theexpandable sealant material, said markers having utility for viewing anddrug delivery.
 3. The method of claim 1, further comprising the step ofincluding marker particles housed within the expandable sealantmaterial, said marker particles having utility for viewing and drugdelivery.